Currently, there are no effective treatments for disease recurrence following allogeneic hematopoietic stem- cell transplant (HSCT). T-cell therapy can target malignancies using mechanisms independent of chemo- radiotherapy, with non-overlapping and generally mild toxicities. Thus, we are investigating adoptive immunotherapy as a strategy to augment the graft-versus-tumor (GVT) effect after allogeneic HSCT. However, this approach has been limited by problems delineating immunogenic epitopes for a large number of HLA alleles, T-cell tolerance to leukemia-associated antigens, and the difficulty of manufacturing patient- specific T cells in a timely manner. As an alternative strategy, we propose to use T cells genetically modified to express a chimeric antigen receptor (CAR) specific a desired tumor antigen independent of MHC. To target B-cell malignancies, we have designed a CAR which re-directs the antigen-specificity of T cells to the B cell lineage-restricted cell-surface molecule CD19. CD19 is expressed on the majority of B-lineage leukemia or lymphoma cells, but is absent on hematopoietic stem cells and non-hematopoietic cells. Genetically modified CD19-specific T cells are activated via chimeric CD3-^ upon CAR binding CD19, resulting in antigen-dependent cytokine production, killing and proliferation. These preclinical data were used to open a Phase I clinical trial (BB-IND 11411) infusing autologous CD19-specific T cells (expressing the first-generation CAR) in patients with relapsed follicular lymphoma. In this grant, we propose a new clinical trial to infuse pre-prepared CD19-specific T cells derived from umbilical cord blood (UCB) in patients with relapsed B-lineage leukemia/lymphoma after allogeneic HSCT. Significantly, this trial will be (i) the """"""""first-in- human"""""""" infusion of CD19-specific T cells after allogeneic HSCT, (ii) the first to infuse T cells expressing a second-generation CAR capable of providing a fully-competent T-cell activation signal (through chimeric CD3-?;and CD28), and (iii) the first to image distribution of genetically modified T cells and their activation status in vivo by positron emission tomography (PET), an example of radio-gene-therapy. We hypothesize that the a priori generation of banks of a homogenous population of UCB-derived HLA-unmatched CD19- specific T-cell clones will permit infusion of T cells in a safe and timely manner in a patient population with little chance of survival. T-cell isolation, genetic modification, and expansion will follow Standard Operating Procedures at MDACC, and T-cell doses will be manufactured in our Good Manufacturing Process (GMP) facility in accordance with quality control/assurance standards mandated by the FDA for a master cell bank. Lav language: T cells will be developed which can destroy B-lineage disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33CA116127-04
Application #
8109372
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (J1))
Program Officer
Merritt, William D
Project Start
2007-06-25
Project End
2013-05-31
Budget Start
2011-08-19
Budget End
2013-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$459,850
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Najjar, Amer M; Manuri, Pallavi R; Olivares, Simon et al. (2016) Imaging of Sleeping Beauty-Modified CD19-Specific T Cells Expressing HSV1-Thymidine Kinase by Positron Emission Tomography. Mol Imaging Biol 18:838-848
Singh, H; Moyes, J S E; Huls, M H et al. (2015) Manufacture of T cells using the Sleeping Beauty system to enforce expression of a CD19-specific chimeric antigen receptor. Cancer Gene Ther 22:95-100
Deniger, Drew C; Yu, Jianqiang; Huls, M Helen et al. (2015) Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations. PLoS One 10:e0128151
Krishnamurthy, Janani; Rabinovich, Brian A; Mi, Tiejuan et al. (2015) Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma. Clin Cancer Res 21:3241-51
Kumaresan, Pappanaicken; Figliola, Mathew; Moyes, Judy S et al. (2015) Automated Cell Enrichment of Cytomegalovirus-specific T cells for Clinical Applications using the Cytokine-capture System. J Vis Exp :
Kumaresan, Pappanaicken R; Manuri, Pallavi R; Albert, Nathaniel D et al. (2014) Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A 111:10660-5
Deniger, Drew C; Maiti, Sourindra N; Mi, Tiejuan et al. (2014) Activating and propagating polyclonal gamma delta T cells with broad specificity for malignancies. Clin Cancer Res 20:5708-19
Rushworth, David; Jena, Bipulendu; Olivares, Simon et al. (2014) Universal artificial antigen presenting cells to selectively propagate T cells expressing chimeric antigen receptor independent of specificity. J Immunother 37:204-13
Bhatnagar, Parijat; Li, Zheng; Choi, Yoonsu et al. (2013) Imaging of genetically engineered T cells by PET using gold nanoparticles complexed to Copper-64. Integr Biol (Camb) 5:231-8
Torikai, Hiroki; Reik, Andreas; Soldner, Frank et al. (2013) Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122:1341-9

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